tbuckley/cabot-search huggingface dataset:
Vector genome loss and epigenetic modifications mediate decline in transgene expression of AAV5 vectors produced in mammalian and insect cells
Authors: Britta Handyside, Ashrafali Mohamed Ismail, Lening Zhang, Bridget Yates, Lin Xie, Choong-Ryoul Sihn, Ryan Murphy, Taren Bouwman, Chan Kyu Kim, Rolando De Angelis, Omair A. Karim, Nicole L. McIntosh, Michael Xavier Doss, Shilpa Shroff, Erno Pungor, Vikas S. Bhat, Sherry Bullens, Stuart Bunting, Sylvia Fong
Journal: Molecular Therapy (2022)

Recombinant adeno-associated virus (rAAV) vectors are often produced in HEK293 or Spodoptera frugiperda (Sf)-based cell lines. We compared expression profiles of "oversized" (∼5,000 bp) and "standard-sized" (4,600 bp) rAAV5-human α1-antitrypsin (rAAV5-hA1AT) vectors manufactured in HEK293 or Sf cells and investigated molecular mechanisms mediating expression decline. C57BL/6 mice received 6 × 1013 vg/kg of vector, and blood and liver samples were collected through week 57. For all vectors, peak expression (weeks 12-24) declined by 50% to week 57. For Sf- and HEK293-produced oversized vectors, serum hA1AT was initially comparable, but in weeks 12-57, Sf vectors provided significantly higher expression. For HEK293 oversized vectors, liver genomes decreased continuously through week 57 and significantly correlated with A1AT protein. In RNA-sequencing analysis, HEK293 vector-treated mice had significantly higher inflammatory responses in liver at 12 weeks compared with Sf vector- and vehicle-treated mice. Thus, HEK293 vector genome loss led to decreased transgene protein. For Sf-produced vectors, genomes did not decrease from peak expression. Instead, vector genome accessibility significantly decreased from peak to week 57 and correlated with transgene RNA. Vector DNA interactions with active histone marks (H3K27ac/H3K4me3) were significantly reduced from peak to week 57, suggesting that epigenetic regulation impacts transgene expression of Sf-produced vectors.
JAK inhibitors for the treatment of adult dermatomyositis: A pilot study
Authors: Océane Landon-Cardinal, Perrine Guillaume-Jugnot, Ségolène Toquet, Nabiha Sbeih, Aude Rigolet, Nicolas Champtiaux, Karim Dorgham, Guy Gorochov, Alain Meyer, Céline Anquetil, Stéphane Barete, Olivier Benveniste, Yves Allenbach
Journal: Journal of the American Academy of Dermatology (2022)
Neurocardiovascular Dysregulation During Orthostasis in Women With Posttraumatic Stress Disorder
Authors: Andrew W. D’Souza, Jeung-Ki Yoo, Ryosuke Takeda, Mark B. Badrov, Elizabeth H. Anderson, Takuro Washio, Carol S. North, Alina Suris, Michael D. Nelson, J. Kevin Shoemaker, Qi Fu
Journal: Circulation (2022)
Primary Aortic Epithelioid Angiosarcomas With Metastatic Disease Detected by 18F-FDG PET/CT
Authors: Meichao Guan, Wei Liu, Jianmin Huang, Lingge Wei, Peng Xie
Journal: Clinical Nuclear Medicine (2022)

Abstract Epithelioid angiosarcoma in the aortic arch with metastatic disease is extremely rare. We report a case of 63-year-old man with suspected bone metastases who underwent 18 F-FDG PET/CT for seeking the potential primary tumor. PET/CT demonstrated intense FDG uptake in the aortic arch with multiple FDG-avid lesions involving the lung, lymph nodes, and bones. Finally, the diagnosis of primary aortic epithelioid angiosarcomas with metastatic disease was confirmed.
Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes
Authors: Jae Won Lee, Elise S. Cowley, Patricia G. Wolf, Heidi L. Doden, Tsuyoshi Murai, Kelly Yovani Olivos Caicedo, Lindsey K. Ly, Furong Sun, Hajime Takei, Hiroshi Nittono, Steven L. Daniel, Isaac Cann, H. Rex Gaskins, Karthik Anantharaman, João M. P. Alves, Jason M. Ridlon
Journal: Gut Microbes (2022)

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-cis orientation in which the sterol rings are “kinked”, as well as small quantities of A/B-trans oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the ”flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.
Publisher Correction: Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice
Authors: Yohan S. S. Auguste, Austin Ferro, Jessica A. Kahng, Andre M. Xavier, Jessica R. Dixon, Uma Vrudhula, Anne-Sarah Nichitiu, Daniele Rosado, Tse-Luen Wee, Ullas V. Pedmale, Lucas Cheadle
Journal: Nature Neuroscience (2022)
Characteristics of High-Need, High-Cost Patients
Authors: Nancy D. Berkman, Eva Chang, Julie Seibert, Rania Ali
Journal: Annals of Internal Medicine (2022)

Accurately identifying high-need, high-cost (HNHC) patients to reduce their preventable or modifiable health care use for their chronic conditions is a priority and a challenge for U.S. policymakers, health care delivery systems, and payers.To identify characteristics and criteria to distinguish HNHC patients.Searches of multiple databases and gray literature from 1 January 2000 to 22 January 2022.English-language studies of characteristics and criteria to identify HNHC adult patients, defined as those with high use (emergency department, inpatient, or total services) or high cost.Independent, dual-review extraction and quality assessment.The review included 64 studies comprising multivariate exposure studies (n = 47), cluster analyses (n = 11), and qualitative studies (n = 6). A National Academy of Medicine (NAM) taxonomy was an initial "best-fit" framework for organizing the synthesis of the findings. Patient characteristics associated with being HNHC included number and severity of comorbid conditions and having chronic clinical conditions, particularly heart disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and hypertension. Patients' risk for being HNHC was often amplified by behavioral health conditions and social risk factors. The reviewers revised the NAM taxonomy to create a final framework, adding chronic pain and prior patterns of high health care use as characteristics associated with an increased risk for being HNHC.Little evidence distinguished potentially preventable or modifiable health care use from overall use.A combination of characteristics can be useful for identifying HNHC patients. Because of the complexity of their conditions and circumstances, improving their quality of care will likely also require an individualized assessment of care needs and availability of support services.Agency for Healthcare Research and Quality. (PROSPERO: CRD42020161179).
A fully degradable transcatheter ventricular septal defect occluder: Towards rapid occlusion and post-regeneration absorption
Authors: Gaoyang Guo, Jinpeng Hu, Fan Wang, Daihua Fu, Rifang Luo, Fanjun Zhang, Cheng Hu, Juan Chen, Xiangbin Pan, Li Yang, Yunbing Wang, Xingdong Zhang
Journal: Biomaterials (2022)
Brugada Syndrome During Infancy and Childhood
Authors: Juan Sieira, Erwin Ströker, Gezim Bala, Ingrid Overeinder, Alexandre Almorad, Mark La Meir, Sonia Van Dooren, Pedro Brugada, Gian-Battista Chierchia, Carlo de Asmundis
Journal: Journal of the American College of Cardiology (2022)
In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations
Authors: Romain Lannes, Mehmet Samur, Aurore Perrot, Celine Mazzotti, Marion Divoux, Titouan Cazaubiel, Xavier Leleu, Anaïs Schavgoulidze, Marie-Lorraine Chretien, Salomon Manier, Didier Adiko, Frederique Orsini-Piocelle, François Lifermann, Sabine Brechignac, Lauris Gastaud, Didier Bouscary, Margaret Macro, Alice Cleynen, Mohamad Mohty, Nikhil Munshi, Jill Corre, Hervé Avet-Loiseau
Journal: Journal of Clinical Oncology (2022)

Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of micro-subclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse.
Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease
Authors: Michael Camilleri, Thyagarajan Subramanian, Fernando Pagan, Stuart Isaacson, Ramon Gil, Robert A. Hauser, Mary Feldman, Mark Goldstein, Rajeev Kumar, Daniel Truong, Nisha Chhabria, Benjamin L. Walter, Jonathan Eskenazi, Robert Riesenberg, Daniel Burdick, Winona Tse, Eric Molho, Bradley Robottom, Perminder Bhatia, Srinath Kadimi, Kevin Klos, David Shprecher, Otto Marquez-Mendoza, Gonzalo Hidalgo, Stephen Grill, George Li, Howard Mandell, Mary Hughes, Sharisse Stephenson, Joel Vandersluis, Michael Pfeffer, Andrew Duker, Vikram Shivkumar, William Kinney, James MacDougall, Michael Zasloff, Denise Barbut
Journal: Annals of Internal Medicine (2022)

Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD.To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation.Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791).Outpatient.150 patients with PD and constipation.ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period.The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]).The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016).Longer treatment periods need to be investigated in future studies.ENT-01 was safe and significantly improved constipation.Enterin, Inc.
Contact Tracing and Exposure Investigation in Response to the First Case of Monkeypox Virus Infection in the United States During the 2022 Global Monkeypox Outbreak
Authors: Erica S. Shenoy, Sharon B. Wright, Deborah N. Barbeau, Lisa A. Foster, Aleah D. King, Patrick S. Gordon, Preeti Mehrotra, Dana E. Pepe, Daniel A. Caroff, Lindsey R. Kim, Shannon E. McGrath, Amy Courtney, Meredith Fahy, David C. Hooper, Kaitlin Macdonald, Eileen F. Searle, Jennifer A. Shearer, Kimon C. Zachary, Lindsay Bouton, Melissa Cumming, Brandi Hopkins, Juliana Jacoboski, Erin Mann, Matthew Osborne, Carley Perez, Jordan Schultz, Sarah Scotland, Elizabeth Traphagen, Lawrence C. Madoff, Catherine M. Brown
Journal: Annals of Internal Medicine (2022)

Background: In May 2022, the first case of monkeypox virus (MPXV) infection in the United States in the current global outbreak was identified. As part of the public health and health care facility response, a contact tracing and exposure investigation was done. Objective: To describe the contact tracing, exposure identification, risk stratification, administration of postexposure prophylaxis (PEP), and exposure period monitoring for contacts of the index patient, including evaluation of persons who developed symptoms possibly consistent with MPXV infection. Design: Contact tracing and exposure investigation. Setting: Multiple health care facilities and community settings in Massachusetts. Participants: Persons identified as contacts of the index patient. Intervention: Contact notification, risk stratification, and symptom monitoring; PEP administration in a subset of contacts. Measurements: Epidemiologic and clinical data collected through standard surveillance procedures at each facility and then aggregated and analyzed. Results: There were 37 community and 129 health care contacts identified, with 4 at high risk, 49 at intermediate risk, and 113 at low or uncertain risk. Fifteen health care contacts developed symptoms during the monitoring period. Three met criteria for MPXV testing, with negative results. Two community contacts developed symptoms. Neither met criteria for MPXV testing, and neither showed disease progression consistent with monkeypox. Among 4 persons with high-risk exposures offered PEP, 3 elected to receive PEP. Among 10 HCP with intermediate-risk exposures for which PEP was offered as part of informed clinical decision making, 2 elected to receive PEP. No transmissions were identified at the conclusion of the 21-day monitoring period, despite the delay in recognition of monkeypox in the index patient. Limitation: Descriptions of exposures are subject to recall bias, which affects risk stratification. Conclusion: In a contact tracing investigation involving 166 community and health care contacts of a patient with monkeypox, no secondary cases were identified. Primary Funding Source: None.
Annals Graphic Medicine - The Bleeding Heart
Authors: Naveed Shah
Journal: Annals of Internal Medicine (2022)

Web ExclusivesNovember 2022Annals Graphic Medicine - The Bleeding HeartFREENaveed ShahNaveed ShahUniversity of Toledo College of Medicine and Life Sciences, Toledo, Ohio (N.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0010 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Toledo College of Medicine and Life Sciences, Toledo, Ohio (N.S.)Disclosures: The author has reported no disclosures of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0010.Author/Illustrator Information: Naveed Shah is a second-year medical student at the University of Toledo College of Medicine and Life Sciences (e-mail, [email protected]adelphi.edu).This article was published at Annals.org on 8 November 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics November 2022Volume 175, Issue 11Page: W150-W151 ePublished: 8 November 2022 Issue Published: November 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Preoperative Evaluation for Noncardiac Surgery
Authors: Kunjam Modha, Christopher Whinney
Journal: Annals of Internal Medicine (2022)

The previous In the Clinic that addressed preoperative evaluation for noncardiac surgery was published in December 2016. This update reaffirms much of the information in the previous version and provides new information that has accumulated since then. The goal of preoperative assessment is to identify the risk for postoperative complications so health care teams can more fully understand how to implement strategies to mitigate risks before and after the operation.
Re: Jihad H. Kaouk, Ethan L. Ferguson, Alp Tuna Beksac, et al. Single-port Robotic Transvesical Partial Prostatectomy for Localized Prostate Cancer: Initial Series and Description of Technique. Eur Urol. 2022;82:551–58
Authors: Minxiong Hu, Liefu Ye
Journal: European Urology (2022)
Intersection of atrial fibrillation and heart failure with mildly reduced and preserved ejection fraction in &gt;400 000 participants in the Get With The Guidelines‐Heart Failure Registry
Authors: Ravi B. Patel, Stephen J. Greene, Haolin Xu, Brooke Alhanti, Pamela Peterson, Clyde W. Yancy, Jonathan Piccini, Gregg C. Fonarow, Muthiah Vaduganathan
Journal: European Journal of Heart Failure (2022)
Highlights From the <i>Circulation</i> Family of Journals
Authors: Sandro Ninni, Thomas Gallot-Lavallée, Cédric Klein, Benjamin Longère, François Brigadeau, Charlotte Potelle, Frederik Crop, Erwann Rault, Camille Decoene, Thomas Lacornerie, Séverine Lals, Claude Kouakam, François Pontana, Dominique Lacroix, Xavier Mirabel, Ananya Singh, Jacek Kwiecinski, Robert Miller, Yuka Otaki, Paul Kavanagh, Serge Van Kriekinge, Tejas Parekh, Heidi Gransar, Konrad Pieszko, Aditya Killekar, Ramyashree Tummala, Joanna Liang, Marcelo Carli, Daniel Berman, Damini Dey, Piotr Slomka, Enrico Romagnoli, Vito Ramazzotti, Francesco Burzotta, Laura Gatto, Valeria Marco, Giulia Paoletti, Giuseppe Biondi-Zoccai, Fernando Alfonso, Filippo Crea, Carlo Trani, Francesco Prati, Jiajun Luo, Muhammad Kibriya, Paul Zakin, Andrew Craver, Liz Connellan, Saira Tasmin, Tamar Polonsky, Karen Kim, Habibul Ahsan, Briseis Aschebrook-Kilfoy, Zhengbao Zhu, Fu-Rong Li, Yiming Jia, Yang Li, Daoxia Guo, Jingsi Chen, Haili Tian, Jing Yang, Huan-Huan Yang, Li-Hua Chen, Kaixin Zhang, Pinni Yang, Lulu Sun, Mengyao Shi, Yonghong Zhang, ; Li, -Qiang Qin, Guo-Chong Chen
Journal: Circulation (2022)

September's highlights from the subspecialty journals span a variety of fascinating topics.The experience with stereotactic radioablation in electrical storm is reported in Circulation: Arrhythmia and Electrophysiology.A deeplearning model of positron emission tomography scans and coronary flow reserve is reported in Circulation: Cardiovascular Imaging.Optical coherence tomography-based measurements of stent expansion and associations with outcomes are presented in Circulation: Cardiovascular Interventions.The impact of accessibility to primary care on hypertension awareness and control is reported in Circulation: Cardiovascular Quality and Outcomes.Last, an analysis of healthy lifestyle factors and their impact on risk of heart failure by background genetic risk for heart failure is presented in Circulation: Heart Failure.
Network reconstruction for trans acting genetic loci using multi-omics data and prior information
Authors: Johann S. Hawe, Ashis Saha, Melanie Waldenberger, Sonja Kunze, Simone Wahl, Martina Müller-Nurasyid, Holger Prokisch, Harald Grallert, Christian Herder, Annette Peters, Konstantin Strauch, Fabian J. Theis, Christian Gieger, John Chambers, Alexis Battle, Matthias Heinig
Journal: Genome Medicine (2022)

Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information.We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data.Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses.We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms.
Cardiovascular Risk Reduction After Renal Denervation According to Time in Therapeutic Systolic Blood Pressure Range
Authors: Felix Mahfoud, Giuseppe Mancia, Roland E. Schmieder, Luis Ruilope, Krzysztof Narkiewicz, Markus Schlaich, Bryan Williams, Flavio Ribichini, Joachim Weil, Hsien-Li Kao, Oriol Rodriguez-Leor, Elias Noory, Tiong Kiam Ong, Thierry Unterseeh, Pedro de Araújo Gonçalves, Andreas Zirlik, Khaled Almerri, Faisal Sharif, Lucas Lauder, Marianne Wanten, Martin Fahy, Michael Böhm
Journal: Journal of the American College of Cardiology (2022)

Renal denervation (RDN) has been shown to lower blood pressure (BP), but its effects on cardiovascular events have only been preliminarily evaluated. Time in therapeutic range (TTR) of BP is associated with cardiovascular events. This study sought to assess the impact of catheter-based RDN on TTR and its association with cardiovascular outcomes in the GSR (Global SYMPLICITY Registry). Patients with uncontrolled hypertension were enrolled and treated with radiofrequency RDN. Office and ambulatory systolic blood pressure (OSBP and ASBP) were measured at 3, 6, 12, 24, and 36 months postprocedure and used to derive TTR. TTR through 6 months was assessed as a predictor of cardiovascular events from 6 to 36 months using a Cox proportional hazard regression model. As of March 1, 2022, 3,077 patients were enrolled: 42.2% were female; mean age was 60.5 ± 12.2 years; baseline OSBP was 165.6 ± 24.8 mm Hg; and baseline ASBP was 154.3 ± 18.7 mm Hg. Patients were prescribed 4.9 ± 1.7 antihypertensive medications at baseline and 4.8 ± 1.9 at 36 months. At 36 months, mean changes were −16.7 ± 28.4 and −9.0 ± 20.2 mm Hg for OSBP and ASBP, respectively. TTR through 6 months was 30.6%. A 10% increase in TTR after RDN through 6 months was associated with significant risk reductions from 6 to 36 months of 15% for major adverse cardiovascular events (P < 0.001), 11% cardiovascular death (P = 0.010), 15% myocardial infarction (P = 0.023), and 23% stroke (P < 0.001). There were sustained BP reductions and higher TTR through 36 months after RDN. A 10% increase in TTR through 6 months was associated with significant risk reductions in major cardiovascular events from 6 to 36 months. (Global SYMPLICITY Registry [GSR] DEFINE; NCT01534299)